BackgroundFemale-pattern hair loss (FPHL) is the most common cause of diffuse hair loss in women. A possible role of non-androgen-dependent mechanisms was suggested. The association between serum 25-hydroxyvitamin D [25-(OH)D] and other hair 0 diseases such as male androgenetic alopecia, telogen effluvium, and alopecia areata has been indicated.ObjectiveThe aim of this study was to evaluate the association of altered serum 25-(OH)D levels in women with FPHL.Patients and methodsWe studied serum 25-(OH)D concentrations among 60 FPHL patients aged from 20 to 35 years in comparison with 60 healthy female controls matched for age, skin phototype, socioeconomic status, and outdoor exposure. Measurements were conducted by the radioimmunoassay technique.ResultsThe mean serum 25-(OH)D level was significantly lower in FPHL patients (14.2 ± 7.31 ng/ml) than in controls (45.90 ± 18.83 ng/ml; P = 0.0001). There was no significant difference between patients with family history and those without family history regarding the mean vitamin D level (15.23 ± 7.56 and 13.6 ± 7.17 ng/ml, respectively; P = 0.363). A significant difference was found between the three Ludwig's degrees regarding the mean vitamin D level (12.96 ± 7.52, 14.16 ± 5.68, and 25 ± 5.35 ng/ml, respectively): between degrees I and III and between degrees II and III.LimitationsThis is a case-control study that supports the hypothesis of an association between vitamin D and FPHL, but does not establish a causal relationship.ConclusionAlteration in the serum 25-(OH)D level, being deficient or insufficient, might play a possible role in the pathogenesis of FPHL.

Female-pattern hair loss (FPHL) is the most common cause of diffuse hair loss in women [1]. It is a result of altered hair follicle cycling and miniaturization, which leads to the transformation of terminal to vellus hair follicles and the production of shorter, finer hair shafts [2].

An androgen-dependent nature has not been proven in FPHL. Most women with FPHL do not have biochemical hyperandrogenism [1], and women without circulating androgens may also develop FPHL [3], suggesting a possible role for non-androgen-dependent mechanisms. This could explain why some women with FPHL do not respond to androgen inhibition therapy [4].

The possible link between serum 25-hydroxyvitamin D {25-(OH)D} and FPHL has not been studied thoroughly; however, there have been recent researches investigating the possible association between serum 25-(OH)D and other hair diseases such as male androgenetic alopecia, telogen effluvium (TE), and alopecia areata [5],[6],[7].

An optimal concentration of vitamin D is necessary to delay aging phenomena, including hair loss [8]. It was suggested that studies conducted on women suffering from FPHL should be investigated to determine whether there is an association of hair loss with altered serum 25-(OH)D levels [9].

Thus, the objective of this study was to evaluate the serum 25-(OH)D level in women with FPHL to determine the association, if any, between the FPHL and serum 25-(OH)D levels.

Patients and methods

This case-control study was carried out on 60 female patients diagnosed with FPHL, aged from 20 to 35 years, skin phototypes III and IV, and 60 healthy female controls matched for age, skin phototype, socioeconomic status, and outdoor exposure. Patients were selected from the dermatology outpatient clinic, Ain Shams University Hospital. Controls were selected from healthy volunteers. Measurements were conducted within a 4-month period (February to May) to minimize seasonal bias in 25-(OH)D levels. An informed consent was provided before participation in the study that was approved by the Ethical Committee of Scientific Research, Faculty of Medicine, Ain Shams University.

All patients and controls were subjected to careful history taking, with a special emphasis on detailed outdoor exposure, socioeconomic status, menstrual history, family history (FH) of FPHL, and drug intake that could alter the serum vitamin D level.

The diagnosis of FPHL was based on clinical findings (the pattern of hair loss: reduction in hair density over the crown and widening of the central part), a positive hair pull test, and a characteristic predominance of dermoscopy abnormalities in the frontal area compared with the occipital area. These abnormalities include an increased proportion of thin and vellus hairs, hair shaft thickness heterogeneity, perifollicular discoloration (hyperpigmentation), and the presence of variable numbers of yellow dots [10]. Patients were graded as stage I, II, or III FPHL according to the clinical examination of the pattern of hair loss that was based on Ludwig's scale [11]. Laboratory investigations including a complete blood count, serum ferritin, dehydroepiandrosterone sulfate, and free testosterone were carried out to exclude iron deficiency or hyperandrogenism. For assessment of 25-(OH)D level, a venous blood sample was taken from all studied groups and quantitative determination of 25-(OH)D was performed using reagents supplied by Diasorin (Stillwater, Minnesota, USA) using the radioimmunoassay technique.

The collected data were revised, coded, tabulated, and introduced to a PC using the Statistical Package for Social Science (SPSS 15.0.1 for Windows; SPSS Inc., Chicago, Illinois, USA). Data were presented, and suitable analysis was performed according to the type of data obtained for each parameter. Parametric numerical data were expressed as mean ± SD and range, whereas median and interquartile range were used for nonparametric numerical data, and frequency and percentage for non-numerical data. The analysis of variance test was used to assess the statistical significance of the difference between more than two study group means.

The post-hoc test is used for comparisons of all possible pairs of group means. Student's t-test was used to assess the statistical significance of the difference between two study group means. The correlation analysis was used to assess the strength of association between two quantitative variables. The correlation coefficient denoted symbolically as 'r' defined the strength and the direction of the linear relationship between two variables. The χ2 -test was used to examine the relationship between two qualitative variables. Fisher's exact test was used to examine the relationship between two qualitative variables when the expected count is less than 5 in more than 20% of cells. The Kruskal-Wallis test was used to assess the statistical significance of the difference between more than two study group ordinal variables. A P-value of 0.05 or less was considered significant (S).

Results

The serum vitamin D level among patients ranged from 5.1 to 33 ng/ml (14.2 ± 7.31 ng/ml), whereas that of the control group ranged from 8 to 80 ng/ml (45.90 ± 18.83 ng/ml). A highly significant difference was found between patients and controls regarding the mean vitamin D level. The serum 25-(OH)D level was significantly lower in FPHL patients than in controls (P = 0.0001; [Figure 1]).

The mean disease duration was 5.3 ± 5.30 years among vitamin D-sufficient patients, whereas it was 5.2 ± 3.63 years among patients with insufficient vitamin D levels and 3.2 ± 2.05 years among vitamin D-deficient patients. There was no significant difference between patients with different vitamin D levels with regard to the mean disease duration.

The mean vitamin D level among patients with no FH was 13.6 ± 7.17 ng/ml and that among patients with positive FH was 15.23 ± 7.56 ng/ml. There was no significant difference between patients with FH and those without FH with regard to the mean vitamin D level (P = 0.363). There were only two patients with sufficient vitamin D levels, and both had no FH of FPHL, representing 5% of all patients with absent FH. There were 11 patients with insufficient vitamin D, and eight of them showed positive FH and the remaining three patients showed absent FH of FPHL. There were 47 patients with deficient vitamin D, and 15 of them showed positive FH and 32 patients showed absent FH of FPHL. There was no significant difference between patients with FH and those without FH regarding sufficient vitamin D levels (P = 0.519), whereas a significant difference was present regarding insufficient vitamin levels (P = 0.015) and a near significant difference was found regarding vitamin D deficiency (P = 0.063; [Table 2]).

Table 2: Relation between family history and differential serum vitamin D levels among patients

According to Ludwig's classification, 34 patients were degree I, 22 patients were degree II, and four patients were degree III. The mean vitamin D level was 12.96 ± 7.52 ng/ml among Ludwig's degree I patients, 14.16 ± 5.68 ng/ml among degree II patients and 25 ± 5.35 ng/ml among degree III patients. A highly significant difference was found between the three Ludwig's degrees regarding the mean serum vitamin D level (P = 0.006; [Table 3]). The post-hoc test revealed differences between degrees I and III and between degrees II and III. There were two patients with sufficient vitamin D levels: one was of grade I and the other patient was grade III. There were 11 insufficient vitamin D patients, five of whom were grade I, three patients were grade II, and the remaining three patients were grade III. There were 47 vitamin D-deficient patients: 28 patients were grade I and 19 patients were grade II. There was no significant difference between patients with different Ludwig's degrees regarding sufficient vitamin D levels (P = 0.130); however, a significant difference was found between them regarding insufficiency (P = 0.026) and deficiency (P = 0.003) of vitamin D [Table 4].

The age of the patient group ranged from 20 to 35 years, with a mean of 26.4 ± 4.51 years, whereas that of the control group ranged from 22 to 35 years, with a mean of 25.85 ± 4.49 years. There was no significant correlation between the age and the mean vitamin D level among the study patients (r = -0.176; P = 0.178). Multivariate analysis to study the effect of vitamin D deficiency/insufficiency on the occurrence of FPHL after adjustment for age showed that women with insufficient/deficient vitamin D levels have 177.7 times the risk of developing FPHL compared with women with sufficient vitamin D levels [Table 5].

Table 5: Multivariate analysis study of the effect of vitamin D deficiency/insufficiency on the occurrence of female-pattern hair loss

The results of the current study support the suggestion that the decreased hair density present in patients with FPHL may possibly be associated with altered levels of serum 25-(OH)D. This was based on finding a highly statistically significant difference between patients and controls regarding the mean serum 25-(OH)D level. These findings most likely indicate the important role of deficient or insufficient serum 25-(OH)D levels in FPHL patients.

Our findings agree with another study [13] that was conducted to evaluate serum 25-(OH)D levels in 42 TE female patients, 38 patients with FPHL, and 40 age-matched healthy female controls. They found that mean serum vitamin D levels in women with TE (28.8 ± 10.5 nmol/l) and FPHL (29.1 ± 8.5 nmol/l) were significantly lower than that in controls (118.2 ± 68.1 nmol/l), suggesting that the reduced hair density seen in chronic TE and FPHL patients may possibly be associated with low serum levels of vitamin D.

Differential vitamin D level assessment revealed a highly significant difference between patients and controls. Deficiency, rather than insufficiency, was more common among patients (47 patients, 78.3%), whereas sufficient levels were found more often among controls (51 controls, 85%), implying the possible role of vitamin D deficiency as one of the important prerequisites to develop hair loss.

FH was absent in 62% of the cases, with the remaining 38% showing a positive FH. There was no significant difference on comparing the mean serum vitamin D level among patients with and without FH. There was no significant difference between patients with FH and those without FH regarding sufficient vitamin D levels, whereas a significant difference was present regarding insufficient vitamin D levels and a near significant difference was found regarding vitamin D deficiency. This may guide us to think that deficient serum 25-(OH)D levels alone might be enough as a triggering factor for developing FPHL. However, insufficiency by itself is not a potent triggering factor to induce FPHL, but might do so when strengthened with a positive FH, as both factors might potentiate FPHL occurrence. Thus, studies on vitamin D receptor expression or intracellular uptake by the hair follicle in FPHL patients with sufficient serum vitamin D levels are recommended to derive the whole picture of vitamin D involvement in developing hair loss.

A highly significant difference between the three Ludwig's degrees with regard to the mean serum 25-(OH)D level was found, which revealed differences between degrees I and III and between degrees II and III. Surprisingly, the mean level was the highest in degree III compared with degrees I and II; the reason for this increase in 25-(OH)D levels in our patients was not known, but we suggest that it might be related to an increased exposure to ultraviolet light due to more decreased scalp hair density. Other authors share similar findings and have further explained that telogen hair follicles do not show melanin synthesis in their undifferentiated melanocytes/melanoblasts, which may ultimately increase ultraviolet exposure and vitamin D synthesis in the skin [5],[14]. In contrast, others [13] have reported significantly higher mean serum levels in mild cases and in moderate cases in comparison with severe cases of FPHL (P = 0.035 and 0.022 respectively); this difference could possibly be explained by our specific patient sample having different patterns of sun exposure.

Serum 25-(OH)D concentrations are commonly believed to decrease with age [15]. However, in this study, we were limited in our ability to examine the relation between the serum 25-(OH)D status and age because the entire cohort was young as participants were collected from the beginning within a narrow age spectrum. A multivariate analysis to study the effect of vitamin D deficiency on the occurrence of FPHL was performed after adjustment for age, and it was shown that women with insufficient/deficient vitamin D levels would have 177.7 times the risk of developing FPHL compared with women with sufficient vitamin D levels.

There were many suggested mechanisms by which vitamin D might have a possible influence on hair follicle cycling and growth. It has been suggested that an optimal concentration of vitamin D is necessary to delay aging phenomena, including hair loss [8],[9]. There was an observable recovery of alopecia areata with reduced vitamin D receptor expression after topical application of calcipotriol, a strong vitamin D analog, after failure of response to various treatments [16]. Moreover, the existence of specific receptors for 1,25-(OH) 2 D 3 in the outer root sheath cells of hair has been indicated, and it has been found that 1,25-(OH) 2 D 3 is a potent inhibitor of proliferation of outer root sheath cells as well as a stimulator of terminal differentiation [17]. Extensive animal studies have suggested that vitamin D 3 analogs act transiently to normalize keratinocytes, which allows production of hair [18],[19]. Furthermore, as vitamin D receptor (VDR) is required for normal hair follicle cycling [20], recently, it was suggested that vitamin D receptors directly or indirectly might regulate the expression of genes required for hair follicle cycling [21].

Taken together, we suggest that an alteration in serum 25-(OH)D levels, whether deficient or insufficient, might play a possible role in the pathogenesis of FPHL. Women with insufficient or deficient 25-(OH)D associated with a positive FH would have a higher risk of developing FPHL compared with women with sufficient levels. Serum 25-(OH)D should be evaluated in women with FPHL to permit an earlier diagnosis of previously unidentified vitamin D insufficiency/deficiency and for the initiation of appropriate treatment. Further large-scale studies are needed to evaluate whether vitamin D supplementation will help in controlling long-term disease activity and in the prevention or delay of disease onset in susceptible (insufficient/deficient) family members of patients with FPHL.